Peptide piperidines

Another competing cyclisation during peptide synthesis is the formation of aspartimides from aspartic acid residues [15]. This problem is common with the aspartic acid-glycine sequence in the peptide backbone and can take place under both acidic and basic conditions (Fig. 9). In the acid-catalysed aspartimide formation, subsequent hydrolysis of the imide-containing peptide leads to a mixture of the desired peptide and a (3-peptide. The side-chain carboxyl group of this (3-peptide will become a part of the new peptide backbone. In the base-catalysed aspartimide formation, the presence of piperidine used during Fmoc group deprotection results in the formation of peptide piperidines. 

Human renin X-ray anaiysis of a weak, non-peptide, piperidine-based HTS hit (26 pM) reveaied a radicaiiy novel mode of binding associated with a iarge conformationai change of the enzyme that had never been observed before. Structure-guided optimization ied to a low nanomolar, drug-like inhibitor. 189... 

The succinimide derivative (234) can be used in peptide synthesis for conversion of amino acids into their succinimide esters (235 Scheme 41) (79CL1265). 3-Substituted mercapto-1,2-benzisothiazole 1,1-dioxides (236) have been recommended as an odourless means of storage of thiols. The latter are readily regenerated by the action of piperidine (81CL1457). 

The Dmab group was developed for glutamic acid protection during Fmoc/r-Bu based peptide synthesis. The group shows excellent acid stability and stability toward 20% piperidine in DMF. It is formed from the alcohol using the DCC protocol for ester formation and is cleaved with 2% hydrazine in DMF at rt. ... 

The Phacm group is stable to the following conditions DIEA-CH2CI2, TFA-CH2CI2, piperidine-DMF, 0.1 M TBAF-DMF, and DBU-DMF for 24 h at It to HF-anisole or / -cresol (9 1) at 0° for 1 h and to TFA-scavengers (phenol, HSCH2CH2SH, p-cresol, anisole) for 2 h at 25°. It is partially stable (>80%) to TFMSA-TFA-/ -cresol for 2 h at 25°. These stability characteristics make the group compatible with BOC- or Fmoc-based peptide synthesis. ... 

This Fmoc analog is prepared from the chloroformate, O-succinimide, or p-nitrophenyl carbonate and is cleaved with 10% piperidine in 1 1 6M guanidine/IPA. It was designed to interact strongly on a column of porous graphitized carbon so as to aid in the purification of peptides after cleavage from the resin. 

The Bnpeoc group was developed as a base-labile protective group for solid-phase peptide synthesis. The carbamate is formed from the O-succinimide (DMF, 10% Na2C03 or 5% NaHC03) and is cleaved using DBN, DBU, DBU/AcOH, or piperidine. ... 

When the Ac group is removed (20% piperidine/DMF or 5% hydrazine/DMF), it becomes the Hmb group that is used to improve solubility and prevent aspar-tamide formation and is readily cleaved with TFA. The related 2-Fmoc-4-methoxybenzyl group has also been prepared and used in peptide synthesis. ... 

P-Lactams have been used as a synthon for the preparation of a vast array of compounds. It has been reported that the reduction of 4-(haloalkyl)azetidin-2-ones with LiAlhL is a powerful method for the synthesis of stereodefined aziridines and azetidines <06OL1101>. However, reduction of 4-(haloalkyl)azetidin-2-ones with chloroalane afforded 2-(haloalkyl)azetidines, which were rearranged to 3,4-cw-disubstituted pyrrolidines and piperidines 32 <060L1105>. During these rearrangements, bicyclic azetidinium intermediates were formed which were ring opened by halides. The synthesis of a peptide-... 

This approach may find application in peptide bond formation that would eliminate the use of irritating and corrosive chemicals such as trifluoroacetic acid and piperidine as has been demonstrated recently for the deprotection of N-boc groups (Scheme 6.7) a solvent-free deprotection of N-tert-butoxycarbonyl group occurs upon exposure to microwave irradiation in the presence of neutral alumina doped with aluminum chloride (Scheme 6.7) [41]. 

Non-peptidic tachykinine antagonists were converted to photoprobe ligands by Ward. First, a piperidine derivative, CP-99,994 (Glaxo) was appended with a diazirine photophore (6, Fig. 7) to study SP (NK1) receptors [74]. A similar modification on a neurokinin A antagonist, SR 48968 (Sanofi) produced a photoligand (5, Fig. 7) in order to investigate NK2 receptor proteins [75]. 

R Dolling, M Beyermann, J Haenel, F Kemchen, E Krause, P Franke, M Brudel, M Bienert. Piperidine-mediated side product formation for Asp(OtBu)-containing peptides. J Chem Soc Chem Commun 853, 1994. 

A Karsltrom, A Unden. A new protecting group for aspartic acid that minimizes piperidine-catalyzed aspartimide formation in Fmoc solid phase peptide synthesis. (3-methylpent-3-yl) Tetrahedron Lett 37, 4234, 1996. 

M Beyermann, M Bienert, H Niedrich, LA Carpino, D Sadat-Aalaee. Rapid continuous peptide synthesis via FMOC amino acid chloride coupling and (4-aminome-thyl(piperidine deblocking. J Org Chem 55, 721, 1990. 

FIGURE 8.15 Alkylamines encountered in peptide synthesis. 1, pyridine 2, 2,4,6-trimethylpy-ridine 3, 2,6-di-ferf-butyl-4-methylpyridine 4, 4-dimethylaminopyridine 5, A-methyl-morpholine, 6, fV-methylpiperidine 7, triethylamine 8, diisopropylethylamine 9, l-diethylaminopropane-2-ol 10, dicyclohexylamine 11, diethylamine 12, piperidine 13, piperazine 14, morpholine 15, l,8-diazabicyclo[5.4.0]undec-7-ene 16, 4-(aminoethyl)piperidine 17, frw(2-aminoethyl)amine 18, 3-dimethylaminopropylamine 19, methylamine 20, dimethy-laminoethane-2-ol 21, 1,2,2,6,6-pentamethylpiperidine 22, l,4-diazabicyclo[2,2,2]octane 23, 7-methyl-1,5,7-triazabicyclo[4,4,0]dec-5 -ene. 

Aminoethyl)piperidine (16) is a base and nucleophile employed for removal of fluorenylmethyl-based protectors during synthesis in solution. The adduct formed with the released moiety can be separated from the peptide ester by extraction into a pH 7.4 phosphate buffer (see Section 7.11). 

LA Carpino, D Sadat-Aalaee, M Beyermann. fnT(2-Aminoethyl)amine as a substitute for 4-(aminoethyl)piperidine in the FMOC/polyamine approach to rapid peptide synthesis. J Org Chem 55, 1673, 1990. 

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